Age-related macular degeneration (AMD) is the leading cause of visual impairment of the elderly in the US. Autophagy is a vital pathway in cellular housekeeping and plays a critical role in the translocation of damaged organelles to the lysosome for degradation. Our data confirm that autophagy plays a critical role in RPE housekeeping and that autophagic efficiency declines with both age and AMD. We conclude that defective autophagy will impair normal RPE function when removal and repair of damaged organelles does not occur. We therefore hypothesize that Decreased autophagy in the RPE plays a major role in retinal aging and the pathogenesis of age-related macular degeneration (AMD). We further postulate that decreased autophagy contributes toward the genesis of lipofuscin, via a combination of reduced autophagic activity and an accumulation of damaged intracellular organelles awaiting autophagic degradation and replacement. We believe that stimulation of the autophagic pathway, which would in turn lead to a reduction in accumulated damaged organelles will reduce retinal aging changes and slow the progression of AMD and lead to the identification of new pharmacological targets. In aim 1, we will characterize the spatial and temporal dynamics of the autophagic pathway in human and animal RPE and determine how this changes with aging and the progression of AMD. In aim 2, we will use primary human RPE cultures to a) characterize the role of oxidative damage on the efficiency of the autophagic pathway and its ability to deal with an increasing burden of damaged intracellular organelles, b) the susceptibility of the RPE to oxidative stress following up or down regulation of the autophagic pathway and c) assess the contribution of autophagic removal of compromised intracellular organelles to lipofuscin formation in the RPE. In aim 3, we will assess the effect of modifying autophagy on in vitro and in vivo models of retinal aging and AMD. We will identify those conditions that best suppress autophagy and generate AMD-like lesions in vitro and translate these to animals and determine if down regulation of expression levels or function of specific elements of the autophagic pathways can induce the AMD-like lesions in wild type mice. Finally, we will determine if enhancing the autophagic pathway can slow the progression of AMD in two mouse models. We believe that characterization of dysfunction in the autophagic pathway in the RPE of AMD retinas will identify new targets in the treatment of this disease. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the major cause of blindness in the elderly, with over 10 million people having reduced vision due to AMD in the US. Understanding the role of autophagy will provide new information on the pathogenesis of AMD and may help develop a sustainable treatment strategy, especially for dry AMD, which is a priority area for the NEI.